3

n-Hexane1

Acute Exposure Guideline Levels

PREFACE

Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances (NAC/AEGL Committee) has been established to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals.

AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distinguished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows:

AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, nonsensory effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure.

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1This document was prepared by the AEGL Development Team composed of Peter Bos (Oak Ridge National Laboratory), Julie Klotzbach (SRC, Inc.), Chemical Manager Alfred Feldt (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protection Agency). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001).



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3 n-Hexane1 Acute Exposure Guideline Levels PREFACE Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guide- line Levels for Hazardous Substances (NAC/AEGL Committee) has been estab- lished to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals. AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distin- guished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows: AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, nonsensory effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. 1 This document was prepared by the AEGL Development Team composed of Peter Bos (Oak Ridge National Laboratory), Julie Klotzbach (SRC, Inc.), Chemical Manager Alfred Feldt (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protection Agen- cy). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are scientifically valid conclu- sions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001). 66

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n-Hexane 67 AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape. AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience life-threatening health effects or death. Airborne concentrations below the AEGL-1 represent exposure concentra- tions that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, nonsen- sory effects. With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGL values represent threshold concentrations for the general public, including susceptible subpopula- tions, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic respons- es, could experience the effects described at concentrations below the corre- sponding AEGL. SUMMARY n-Hexane is a colorless liquid with a slightly disagreeable, gasoline-like odor. It dissolves slightly in water. The lower explosive limit of n-hexane is 1.1%. n-Hexane is produced from natural gas and crude oil. Its main use in in- dustry is in products known as solvents. The major uses for these solvents are in food processing to extract vegetable oils from crops, as cleaning agents in the printing, textile, furniture, and shoemaking industries (used in special glues), and in the manufacture of pharmaceuticals. Because of their easily accessibility, solvents and glues containing n-hexane are often used in inhalant abuse. Human data on the acute toxicity of n-hexane are extremely limited and are insufficient for setting AEGL values. The data show that the acute toxicity of n-hexane is very low. No cases of lethality were reported after inhalation of n-hexane or n-hexane-containing mixtures, not even in solvent abuse. Further- more, no severe clinical signs were reported in human volunteers after acute exposure to n-hexane both at rest and during physical exercise. Genotoxic and carcinogenic effects of the chemical have not been examined in humans. Chron- ic exposure to n-hexane frequently results in degenerative distal axonopathy in the peripheral nervous system, but this effect is not relevant for acute exposures. Two LC50 (lethal concentration, 50% lethality) values for n-hexane have been reported for rats, but the original studies from which they were derived could not be obtained. Findings in toxicokinetic studies appear to have discrep- ancies with the LC50s. Visible signs of acute toxicity from n-hexane are general- ly associated with effects on the nervous system, such as reduced respiration, ptosis, myoclonic seizures, ataxia, decreased motor activity, sedation, laying

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68 Acute Exposure Guideline Levels down in a side position, and narcosis. Rats exposed to n-hexane exhibited acute effects on the brain and lungs and reversible lesions in the testis. The most sig- nificant effect in developmental and reproduction studies of n-hexane was a transient retardation in the growth of live pups; however, this effect is consid- ered to be a result of repeated exposure. In general, n-hexane is not mutagenic in vitro although some positive results were obtained. n-hexane is not mutagenic in mice, but morphologic alterations in sperm, as well as chromatid breaks in bone marrow cells, were reported in rats. The limited information available on the carcinogenicity found hepatocellular neoplasms in mice and papillary tumors in the bronchiolar epithelium of rabbits exposed to n-hexane. Because of insufficient human and animal data addressing the level of ef- fects defined by AEGL-1, no AEGL-1 values are recommended for n-hexane. Human and animal data indicate that central nervous system (CNS) de- pression is the most relevant adverse effect of acute exposure to n-hexane. How- ever, adequate human data for evaluating concentration-response relationships for AEGL-2 effects are not available. Reporting insufficiencies in rat studies and confounding methodologic issues in studies of mice severely limit confidence in identifying no-effect levels for AEGL-2 effects. Although data are not available to define the concentration-response curve for n-hexane, a steep concentration- response relationship is observed for butane, a structural analog of n-hexane and central nervous system depressant (NRC 2012). On this basis, at steep concen- tration-response relationship is also expected for n-hexane. For chemicals with a steep concentration-response curve, AEGL-2 values may be derived by reducing AEGL-3 values by one-third (NRC 2001). AEGL-3 values were based on a kinetic study of male Sprague-Dawley rats exposed to n-hexane at an actual concentration of 86,222 ± 1,330 ppm for 10, 15, 20, 25, or 30 min (Raje et al. 1984). Although the study focused on blood n-hexane concentrations, some toxicity data were provided; rats exposed for 25 or 30 min showed visible signs of toxicity (ataxia and decreased motor activity), but no deaths. From these results, a 30-min exposure at 86,222 ppm in rats was chosen as the point of departure for AEGL-3 values. Considering data on hu- mans, rats, and mice, a total uncertainty factor of 10 appears to be sufficient for toxicokinetic and toxicodynamic differences between individuals and interspe- cies differences. The effects are attributed to n-hexane itself and no relevant differences in kinetics are assumed, so only small interindividual differences are expected. Steady-state blood concentrations for n-hexane will be reached in ap- proximately 30 min. Thus, the 30-min AEGL-3 value was adopted as the 1-, 4-, and 8-h AEGL-3 values. The 10-min AEGL-3 value was derived from the 30- min value by time scaling using the equation Cn × t = k, with n = 3. All of the AEGL-3 values are higher than 50% of the lower explosive limit for n-hexane and the 10-min value is higher than the lower explosive limit, so safety consid- erations against the hazard of explosion must be taken into account. AEGL values are summarized in Table 3-1.

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n-Hexane 69 TABLE 3-1 AEGL Values for n-Hexane End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1 NR NR NR NR NR Insufficient (nondisabling) data AEGL-2 4,000 ppma 2,900 ppma 2,900 ppma 2,900 ppma 2,900 ppma One-third of (disabling) (14,000 (10,000 (10,000 (10,000 (10,000 AEGL-3 values mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) AEGL-3 See See See See See No lethality in (lethal) belowb belowc belowc belowc belowc rats (Raje et al. 1984) Abbreviations: NR, not recommended because of insufficient data. a The AEGL-2 value is higher than 10% of the lower explosive limit of n-hexane in air of 1.1% (11,000 ppm). Therefore, safety considerations against the hazard of explosion must be taken into account. b The 10-min AEGL-3 value of 12,000 ppm (42,000 mg/m3) is higher than the lower ex- plosive limit of n-hexane in air of 1.1% (11,000 ppm). Therefore, extreme safety consid- erations against the hazard of explosion must be taken into account. c The AEGL-3 values for the 30-min, 1-h, 4-h, and 8-h durations are each 8,600 ppm (30,000 mg/m3), which is higher than 50% of the lower explosive limit of n-hexane in air of 1.1% (11,000 ppm). Therefore, extreme safety considerations against the hazard of explosion must be taken into account. 1. INTRODUCTION n-Hexane is a chemical isolated from natural gas and crude oil (WHO 1991; ATSDR 1999). Pure n-hexane is a colorless, volatile liquid with a slightly disagreeable, gasoline-like odor. It evaporates very easily in air and dissolves only slightly in water. N-Hexane is highly flammable, and its vapors can be ex- plosive (ATSDR 1999). Pure n-hexane is used in laboratories (WHO 1991; ATSDR 1999). Most of the n-hexane used in industry is mixed with similar chemicals in products known as solvents. Common names for some of these solvents are commercial hexane, mixed hexanes, petroleum ether, and petroleum naphtha (ATSDR 1999). Commercial hexane is mainly a mixture of hexane isomers and related 6- carbon compounds, and has an n-hexane content varying between 20 and 80% (WHO 1991). Several hundred million pounds of n-hexane are produced in the United States each year in the form of these solvents (WHO 1991; ATSDR 1999). The major use for these solvents is in food processing to extract vegeta- ble oils from crops such as soybeans, flaxseed, peanuts, safflower seed, corn germ, and cottonseed. They are also used as cleaning agents in the printing, tex- tile, furniture, and shoemaking industries. Certain kinds of special glues used in the roofing and shoe and leather industries also contain n-hexane. Several other products containing n-hexane are gasoline, low-temperature thermometers, ad- hesives, and lacquers. n-Hexane is also present in rubber cement. It is further used in the manufacture of pharmaceuticals. Selected physical and chemical properties of n-hexane are presented in Table 3-2.

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70 Acute Exposure Guideline Levels TABLE 3-2 Chemical and Physical Data for n-Hexane Parameter Value Reference Synonyms Hexane; hexyl hydride ATSDR 1999 CAS registry no. 110-54-3 ACGIH 2001 Chemical formula C6H14 Lide 1999 Molecular weight 86.18 Lide 1999 Physical state Liquid O’Neil et al. 2006 Color Colorless O’Neil et al. 2006 Odor Faint, peculiar odor O’Neil et al. 2006 Melting point -95 to -100°C O’Neil et al. 2006 Boiling point 69°C O’Neil et al. 2006 Vapor density (air = 1) 2.97 WHO 1991 Liquid density (water = 1) 0.660 O’Neil et al. 2006 Solubility in water Insoluble; 9.5 mg/L ATSDR 1999; O’Neil et al. 2006 Vapor pressure 138 mm Hg @ 24°C; WHO 1991; 150 mm Hg @ 25°C ATSDR 1999 Flammability Highly flammable ATSDR 1999 Explosive Lower explosive limit = 1.1% WHO 1991 3 Conversion factors 1 mg/m = 0.284 ppm WHO 1991 1 ppm = 3.52 mg/m3 Commercial hexanes are manufactured by two-tower distillation of a suit- able hydrocarbon feedstock (WHO 1991). The feedstock may be straight-run gasoline distilled from crude oil or natural gas. Hexanes are also obtained from the remains of catalytic reformates after the removal of aromatics. Very pure n-hexane can be produced from hexane mixtures by absorption on molecular sieves. n-Hexane evaporates easily, so the greatest potential for exposure is through inhalation. Because gasoline contains n-hexane, almost everyone is ex- posed to small amounts of the chemical in the air. A concentration of 2 ppb in the air has been reported for n-hexane (ATSDR 1999). Foods, drinking water, and even cooking oils processed with solvents containing n-hexane do not gen- erally contain n-hexane or contain only very small amounts. Exposure to n-hexane most frequently occurs among industrial workers in occupational set- tings (for example, refinery workers, shoe and footwear assembly workers, ball makers, laboratory technicians, and carpenters). Some people known as “sniff- ers” inhale volatile chemicals deliberately for their euphoric properties (reviews of Seppäläinen [1988] and Ritchie et al. [2001]). Exposure can also occur in the home if products containing n-hexane are used without proper ventilation.

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n-Hexane 71 Concentrations of n-hexane measured in extraction facilities were 0.9-97 ppm (olive extraction plants) and 4.4-13.2 ppm (soybean extraction facility) (WHO 1991). Concentrations measured for outside operators and transport driv- ers were 0.13 ± 0.17 ppm and 0.33 ± 0.25 ppm, respectively. Maximum time- weighted average (TWA) (8 h) concentrations of n-hexane at an extraction facil- ity were found to be 26 ppm. 2. HUMAN TOXICITY DATA Many studies of toxicologic effects of n-hexane in humans are available. However, most of these studies concerned industrial workers or substance abus- ers repeatedly exposed for long periods of time to commercial hexane. Commer- cial hexane generally contains 20-80% n-hexane, in addition to hexane isomers and small amounts of related carbon compounds (e.g., cyclopentane, cyclohex- ane, pentane, and heptane) and other chemicals (e.g., acetone, methyl ethyl ke- tone, and toluene). Often co-exposure to other solvents was also present. Since most of the studies concern repeated exposure to solvents with a low percentage of n-hexane (not pure), they were considered of little or no relevance for deriv- ing AEGL values for n-hexane are not discussed in detail. However, it is note- worthy that no lethality was reported in humans abusively exposed to n-hexane or commercial hexane. The main toxic effect reported for n-hexane in human studies is degenera- tive distal axonopathy in the peripheral nervous system, which is caused by the main toxic metabolite 2,5-hexanedione (2,5-HD). Peripheral neuropathy devel- ops in workers who are occupationally exposed to rather high concentrations of n-hexane for months (ATSDR 1999). Therefore, this effect is a result of chronic exposure to n-hexane and is not relevant for deriving AEGL values. 2.1. Acute Lethality 2.1.1. Case Reports No case reports of human lethality from acute exposure to n-hexane (pure or commercial) were found. 2.2. Nonlethal Toxicity 2.2.1. Case Reports No relevant case reports of nonlethal toxicity from n-hexane were found. 2.2.2. Experimental Studies Nelson et al. (1943) exposed human volunteers in a chamber (approxi- mately 10 subjects; both sexes) to n-hexane at nominal concentrations of up to

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72 Acute Exposure Guideline Levels 500 ppm for 3-5 min. Exposure was well tolerated and there were no subjective complaints. Four Caucasian male volunteers (22-52 years old; no occupational expo- sure to organic solvents) were exposed (whole body) for 2 h to n-hexane (purity 99%) at an actual concentration of 54.2 (±0.8) ppm during light physical exer- cise (50 W) on a bicycle ergometer (Shibata et al. 2002). Subjects rated the se- verity (somewhat, rather, quite, and very) of 10 main symptoms frequently asso- ciated with solvent exposure in a questionnaire. Symptoms in the questionnaire included: ocular discomfort, runny nose, discomfort in throat or airways, head- ache, fatigue, nausea, dizziness, feeling of being intoxicated, difficulty in breath- ing, and odor of solvents. Ratings for all symptoms except odor were below 10% of the whole scale and corresponded to verbal ratings of “not at all” and “hardly at all”. In addition, several toxicokinetic studies with volunteers were performed. Although the studies did not focus on adverse health effects, no mention of such effects was made. These studies are briefly described. No adverse clinical effects or subjective complaints were reported in an absorption study with 10 volunteer students (healthy Japanese men and women; 18- to 25-years old) after a 4-h exposure (whole body) to n-hexane (purity not specified) at actual concentrations of 87-122 ppm (Nomiyama and Nomiyama 1974). Veulemans et al. (1982) exposed healthy male subjects (25- to 35-years old) to n-hexane (purity unknown) at 100 and 200 ppm (360 and 720 mg/m3, respectively) for 4 h at rest and at 100 ppm (360 mg/m3) for 3 h under exertion (up to 100 W). No adverse clinical effects or subjective complaints were report- ed. No adverse clinical effects or subjective complaints were also reported in healthy male volunteers (19- to 26-years old) exposed twice (nose only; in a sitting position) to n-hexane (purity 99%) at 60 ppm with a 4-h interval (van Engelen et al. 1997). Mean exposure durations were 15.5 min and 3.91 h, re- spectively. 2.2.3. Occupational and Epidemiological Studies The group of Perbellini and Brugnone has published many reports on n-hexane in occupational settings. In one study, grasp samples of breathing zone air were collected from 20 workers (18 men and 2 women) employed in a shoe upper factory after 60, 165, 195, and 270 min. Average n-hexane concentrations were 99 ppm (349 mg/m3), 150 ppm (531 mg/m3), 167 ppm (589 mg/m3), and 214 ppm (755 mg/m3), respectively (Brugnone et al. 1978). No adverse clinical symptoms were reported. In a second study, the breathing zone air of workers in a shoe factory was collected at different time points (duration of sampling not specified). An average n-hexane concentration of 117 ppm (411 mg/m3) was

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n-Hexane 73 reported (mean of 76 air samples, with a maximum concentration of 480 ppm [1,700 mg/m3]) (Perbellini et al. 1980). Ten healthy workers (18-30 years old) employed in a shoe factory were shown to be exposed to n-hexane at an 8-h TWA of 69 ppm (243 mg/m3) (range 2-325 ppm [8-1,143 mg/m3]) (Mutti et al. 1984). No adverse clinical signs were reported. No adverse clinical effects were also reported in four healthy shoe factory workers (women, 41-54 years old) exposed during four working days to a mean concentration of n-hexane in the breathing zone of 1.9-31 ppm (6.7-108.7 mg/m3). The exposure period was preceded by four days without exposure and followed by two exposure-free days (Ahonen and Schimberg 1988). 2.3. Neurotoxicity No neurotoxicity studies of acute exposure to n-hexane in humans were found. 2.4. Developmental and Reproductive Toxicity No studies on developmental and reproductive toxicity of n-hexane in hu- mans are available. However, it has been reported that on the basis of data from experimental animals and according to the Nordic criteria, n-hexane has been classified into Group 1B: “The substance should be regarded as toxic to human reproduction” (Hansen 1992). 2.5. Genotoxicity The genotoxicity of n-hexane has been evaluated by two organizations (WHO 1991; ATSDR 1999). Both evaluations reported only one in vitro test of n-hexane in human cells; no increase in unscheduled DNA synthesis was found in an assay using human lymphocytes. Genotoxic effects have not been exam- ined in humans after n-hexane exposure. 2.6. Carcinogenicity No epidemiological studies of occupational exposure to n-hexane and can- cer were found, which was consistent with the reviews by WHO (1991) and ATSDR (1999). 2.7. Summary of Human Data In humans, n-hexane is of low acute toxicity. No cases of lethality were reported after inhalation of n-hexane or commercial hexane. Furthermore, no

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74 Acute Exposure Guideline Levels severe clinical signs were reported by volunteers after acute exposure at the highest n-hexane concentrations tested (200 ppm for 4 h at rest and 100 ppm for 1 h under physical exercise [20-100W]). The only symptom reported at more than 10% on a rating scale by volunteers exposed for 2 h to n-hexane at an actu- al concentration of 54.2 ppm while performing low physical exercise (50 W) was detection of the odor of n-hexane. Corresponding to the evaluations of WHO (1991) and ATSDR (1999), no studies on genotoxicity in humans were located. Only a negative unscheduled DNA synthesis assay using human lymphocytes has been reported. Although genotoxic effects have not been examined in humans after n-hexane exposure, genotoxicity in humans cannot be excluded because some positive results were reported in limited animal studies (polyploidy, structural aberrations, and sister chromatid exchanges in in vitro tests with mammalian cells, and morphologic alterations in sperm and chromatid breaks in bone marrow cells in studies of rats) (see Section 3.5). Consistent with the WHO (1991) and ATSDR (1999) reviews, no epide- miologic studies of occupational exposure to n-hexane and cancer in humans were found. However, carcinogenicity cannot be excluded because limited stud- ies in experimental animals have reported hepatocellular neoplasms (adenoma and carcinoma) in mice and papillary tumors in the bronchiolar epithelium of rabbits. 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality 3.1.1. Rats Little data were available on acute lethality of n-hexane in rats. Two LC50 values were reported, but lacked details on experimental conditions. A 1-h LC50 of 76,900 ppm for rats was reported in a neurotoxicity study by Pryor et al. 1982 (see Section 3.2.1) and a 4-h LC50 of 48,000 ppm is mentioned in a review by Couri and Milks (1982) without any details or a reference. Some studies on the toxicokinetics and metabolism (exposure durations of 10 min to 10 h) were available, in which high concentrations of n-hexane (10,000-86,222 ppm) were used (Böhlen et al. 1973; Baker and Rickert 1981; Bus et al. 1982; Raje et al. 1984; see Section 4.1 for details). No mortality was reported in these studies, not even at concentrations as high as 86,222 ppm for 30 min (male Sprague-Dawley rats; whole-body exposure) (Raje et al. 1984) or 48,280 ppm for 10 h (female albino rats; whole-body exposure; purity of n-hexane not specified) (Böhlen et al. 1973). No mortality was reported in rats exposed to n-hexane at 48,000 ppm for 10 min, 6 times per day (at least 50 min between exposures), 5 days per week for 10 weeks, followed by an additional 8 weeks at an increased frequency of 12

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n-Hexane 75 exposures per day (10-min exposure, 20-min no exposure) and another 4 weeks at a frequency of 24 times per day (10-min exposure, 5-min no exposure). In addition, one repeated exposure study on metabolism was available in which high concentrations of n-hexane were used. In this study, male Fischer rats were exposed (whole body) for 12 weeks to n-hexane (purity 95%) at a concentration of either 48,000 ppm for 10 min every 30 min, 8 h/day, 5 days/week or 40,000 ppm for 10 min every 30 min with a background of n-hexane at 4,000 ppm con- tinuously, 8 h/day, 5 days/week (Howd et al. 1982). No mortality was reported for either exposure regimen. 3.1.2. Mice Fühner (1921) studied the narcotic action of n-hexane (pure, but percent- age not specified) prepared from coal oil (initial concentrations approximately 34,800, 38,210, 41,620, 43,750, and 51,990 ppm [123, 134, 147, 154, and 183 g/m3, respectively]) and n-hexane prepared from propyl iodide (initial concen- trations approximately 37,640 and 40,060 ppm [132 and 141 g/m3, respective- ly]) in white mice (sex and strain not specified). Animals were exposed whole- body in a so-called ‘narcotic bottle’ in which a watch glass was present for evaporation of required volumes of n-hexane. In this bottle, 1-2 mice could be exposed at the same time, but the number of animals exposed at each concentra- tion was not specified. Animals were exposed for different durations (20-127 min) until they were removed or until they died. n-Hexane from coal oil induced mice to lay down in a side position without standing up after shaking the expo- sure chamber (narcotic action) after 34-90 min at the lowest concentration (34,800 ppm) and after 10 min at the highest concentration (51,990 ppm) (dose- dependent effect). Loss of reflexes occurred only at higher concentrations of approximately 38,210, 43,750, and 51,990 ppm after 75 min (1/1), 39 and 57 min (2/2), and 20 and 31 min (2/3), respectively. Animals losing reflexes died after exposure for 127 min (1/1), 73 and 119 min (2/2), and 51 min (1/2), respec- tively. At 51,990 ppm, one of three mice died very rapidly after 9 min with te- tanic convulsions. The minimal fatal dose of n-hexane was approximately 38,210 ppm for 127 min. n-Hexane showed a marked depressant effect on respi- ration. Comparative results were obtained with n-hexane prepared from propyl iodide. Loss of reflexes occurred within 34 and 42 min (2/2) at 37,640 ppm and within 23 min at 40,060 ppm (dose-dependent effect). The minimal fatal con- centration was 37,640 ppm; animals died after 39 and 45 min (2/2). No mortality was observed in mice exposed to n-hexane at 40,060 ppm for 26 min. This study could not be used for quantitative analysis, because mice were exposed in a closed system and n-hexane concentration as well as the oxygen concentration will have decreased during exposure while carbon dioxide will have increased; the number of animals exposed at each exposure concentration was unknown; and respiration rate steadily decreased during exposure.

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76 Acute Exposure Guideline Levels These results appeared to be confirmed by Lazarew (1929) who deter- mined a minimal narcotic concentration of n-hexane causing mice (sex and strain not specified) to lay down in a side position of approximately 28,000 ppm (100 g/m3) and a minimal fatal concentration of 34,000-43,000 ppm (120-150 g/m3). Exposures were for 2h, but the purity of the n-hexane and whether con- centrations were actual or nominal concentrations were not specified. Reflexes in mice frequently persisted until death. These results showed a very small mar- gin between narcotic and fatal concentration. Exposures were in a closed sys- tem, similar to the experiments by Fühner (1921). Ten male NMRI mice were exposed to n-hexane under static conditions (Krämer et al. 1974); 3.2 mL of n-hexane was added in a 25-L glass box (equal to an initial concentration of about 24,000 ppm) and exposure was for at least 24 h. No mortality was reported under these conditions. The only adverse effect mentioned was that exposed mice suffered from body weight loss compared with controls. Groups of four Swiss mice (sex not specified) were exposed head-only for 5 min to n-hexane (purity ≥99%) at nominal concentrations of 1,000, 2,000, 4,000, 8,000, 16,000, 32,000, and 64,000 ppm. No mention was made of wheth- er concentrations were monitored during exposure (Swann et al. 1974). Test conditions were the same as those in the sensory irritation test (determination of the concentration that reduces the respiratory rate by 50% [RD50]), and were considered to be screening tests. Mice were placed in individual plethysmo- graphs to investigate effects on pulmonary physiology during exposure. Mice had light anesthesia at 16,000 ppm, whereas at 32,000 ppm they became directly anesthetized with occasional sporadic body movements. At 64,000 ppm, all mice had respiratory arrest within 4.5 min. During exposure at 64,000 ppm, res- piration was highly irregular; excitation was followed by light anesthesia with body movements, irregular respiration, an increase in inspiratory effort, and a decrease in the expiratory effort. Respiratory arrest occurred at the end of inspi- ration. No convulsions were observed. No information on the methods used to assess anaesthesia was provided. Animals in this study were restrained, which could potentially affect assessments of n-hexane-induced anaesthesia, adding uncertainty to determination of effect levels for AEGL-2 value. A summary of relevant lethality data is presented in Table 3-3. 3.2. Nonlethal Toxicity 3.2.1. Rats Three groups of 12 male Fischer rats (six or nine “intact animals” and six or three “surgically prepared animals” for neurologic testing) were intermittently exposed (whole body) to n-hexane (labeled; purity ≥95%) at target concentra- tions of 24,000 (one group) and 48,000 ppm (two groups) (Pryor et al. 1982).

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104 Acute Exposure Guideline Levels TABLE 3-9 Continued Exposure Duration Guideline 10 min 30 min 1h 4h 8h IDLH (NIOSH)d 1,100 ppm (3,880 mg/m3) TLV -TWA 50 ppm (ACGIH )e (180 mg/m3) REL-TWA 50 ppm (NIOSH)f (180 mg/m3) PEL-TWA 500 ppm (OSHA)g (1,800 mg/m3) REL-STEL 510 ppm (NIOSH)h (1,800 mg/m3) MAK 50 ppm (Germany)i (180 mg/m3) MAK Peak 180 ppm Limit (Germany)j (630 mg/m3) MAC (The 25 ppm Netherlands)k (90 mg/m3) Abbreviations: NR, not recommended. a The AEGL-2 value is higher than 10% of the lower explosive limit of n-hexane in air of 1.1% (11,000 ppm). Therefore, safety considerations against the hazard of explosion must be taken into account. b The 10-min AEGL-3 value of 12,000 ppm (42,000 mg/m3) is higher than the lower ex- plosive limit of n-hexane in air of 1.1% (11,000 ppm). Therefore, extreme safety consid- erations against the hazard of explosion must be taken into account. c The AEGL-3 values for the 30-min, 1-h, 4-h, and 8-h durations are each 8,600 ppm (30,000 mg/m3), which is higher than 50% of the lower explosive limit of n-hexane in air of 1.1% (11,000 ppm). Therefore, extreme safety considerations against the hazard of explosion must be taken into account. d IDLH (immediately dangerous to life or health, National Institute for Occupational Safe- ty and Health) (NIOSH 1994) represents the maximum concentration from which one could escape within 30 min without any escape-impairing symptoms, or any irreversible health effects. e TLV-TWA (threshold limit value - time weighted average, American Conference of Governmental Industrial Hygienists) (ACGIH 2001, 2012) is the time-weighted average concentration for a normal 8-h workday and a 40-h workweek, to which nearly all work- ers may be repeatedly exposed, day after day, without adverse effect. f REL-TWA (recommended exposure limit - time weighted average, National Institute for Occupational Safety and Health) (NIOSH 2011) is defined analogous to the ACGIH TLV-TWA. g PEL-TWA (permissible exposure limit - time weighted average, Occupational Safety and Health Administration) (29 CFR 1910.1000 [2006]) is defined analogous to the ACGIH TLV-TWA, but is for exposures of no more than 10 h/day, 40 h/week. h REL-STEL (recommended exposure limit - short term exposure limit, National Institute for Occupational Safety and Health) (NIOSH 1977) is defined as a 15-min TWA expo- sure that should not be exceeded at any time during the workday.

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n-Hexane 105 i MAK (maximale arbeitsplatzkonzentration [maximum workplace concentration], Deutsche Forschungsgemeinschaft [German Research Association]) (DFG 2005) is de- fined analogous to the ACGIH TLV-TWA. j MAK Spitzenbegrenzung (peak limit) (German Research Association (DFG2003) consti- tutes the maximum average concentration to which workers can be exposed for a period up to 30 min with no more than two exposure periods per work shift; total exposure may not exceed 8-h MAK. k MAC (maximaal aanvaaarde concentratie [maximal accepted concentration], Dutch Expert Committee for Occupational Standards, The Netherlands) (MSZW 2004) is de- fined analogous to the ACGIH TLV-TWA. 9. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 2001. n-Hexane (CAS Reg. No. 110-54-3). Documentation of the Threshold Limit Values and Bio- logical Exposure Indices, 7th Ed. American Conference of Governmental Industri- al Hygienists, Cincinnati, OH. ACGIH (American Conference of Governmental Industrial Hygienists). 2012. n-Hexane (CAS Reg. No. 110-54-3). Threshold Limit Values and Biological Exposure Indi- ces. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. Ahonen, I., and R.W. Schimberg. 1988. 2,5-Hexanedione excretion after occupational exposure to n-hexane. Br. J. Ind. Med. 45(2):133-136. ATSDR (Agency for Toxic Substances and Disease Registry). 1999. Toxicological Profile for n-Hexane. U.S. Department of Health and Human Services, Public Health Ser- vice, Agency for Toxic Substances and Disease Registry, Atlanta, GA. July 1999 [online]. Available: http://www.atsdr.cdc.gov/ToxProfiles/tp113.pdf [accessed Jan. 16, 2013]. Baker, T.S., and D.E. Rickert. 1981. Dose-dependent uptake, distribution, and elimina- tion of inhaled n-hexane in the Fischer-344 rat. Toxicol. Appl. Pharmacol. 61(3):414-422. Böhlen, P., U.P. Schlunegger, and E. Läuppi. 1973. Uptake and distribution of hexane in rat tissues. Toxicol. Appl. Pharmacol. 25(2):242-249. Brugnone, F., L. Perbellini, L. Grigolini, and P. Apostoli. 1978. Solvent exposure in a shoe upper factory. I. n-Hexane and acetone concentrations in alveolar and envi- ronmental air and in blood. Int. Arch. Occup. Environ. Health 42(1):51-62. Bus, J.S., E.L. White, R.W. Tyl, and C.S. Barrow. 1979. Perinatal toxicity and metabo- lism of n-hexane in Fischer-344 rats after inhalation exposure during gestation. Toxicol. Appl. Pharmacol. 51(1):295-302. Bus, J.S., D. Deyo, and M. Cox. 1982. Dose-dependent disposition of n-hexane in F-344 rats after inhalation exposure. Fundam. Appl. Toxicol. 2(5):226-229. Cavender, F.L., H.W. Casey, H. Salem, D.G. Graham, J.A. Swenberg, and E.J. Gralla. 1984. A 13-week vapor inhalation study of n-hexane in rats with emphasis on neu- rotoxic effects. Fundam. Appl. Toxicol. 4(2 Pt.1):191-201. Couri, D., and M. Milks. 1982. Toxicity and metabolism of the neurotoxic hexacarbons n- hexane, 2-hexanone, and 2,5-hexanedione. Annu. Rev. Pharmacol. Toxicol. 22:145- 166. De Jongh, J., H.J. Verhaar, and J.L. Hermens. 1998. Role of kinetics in acute lethality of nonreactive volatile organic compounds (VOCs). Toxicol. Sci. 45(1):26-32.

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106 Acute Exposure Guideline Levels De Martino, C., W. Malorni, M.C. Amantini, P. Scorza Barcellona, and N. Frontali. 1987. Effects of respiratory treatment with n-hexane on rat testis morphology. I. A light microscopic study. Exp. Mol. Pathol. 46(2):199-216. DFG (Deutsche Forschungsgemeinschaft). 2003. List of MAK and BAT Values 2003. Maximum Concentrations and Biological Tolerance Values at the Workplace Re- port No. 39. Weinheim, Federal Republic of Germany: Wiley-VCH. DFG (Deutsche Forschungsgemeinschaft). 2005. List of MAK and BAT Values 2005. Maximum Concentrations and Biological Tolerance Values at the Workplace Re- port Report No. 41. Weinheim, Federal Republic of Germany: Wiley VCH. Drummond, I. 1993. Light hydrocarbon gase: A narcotic, asphyxiant, or flammable haz- ard? Appl. Occup. Environ. Hyg. 8(2):120-125. Dunnick, J.K., D.G. Graham, R.S. Yang, S.B. Haber, and H.R. Brown. 1989. Thirteen- week toxicity study of n-hexane in B6C3F1 mice after inhalation exposure. Toxi- cology 57(2):163-172. Edelfors, S., and A. Ravn-Jonsen. 1985. Calcium uptake in rat brain synaptosomes after short-term exposure to organic solvents: A pilot study. Acta Pharmacol. Toxicol. 56(5):431-434. Fedtke, N., and H.M. Bolt. 1986. Methodological investigations on the determination of n-hexane metabolites in urine. Int. Arch. Occup. Environ. Health 57(2):149-158. Fedtke, N., and H.M. Bolt. 1987a. 4,5-Dihydroxy-2-hexanone: A new metabolite of n-hexane and of 2,5-hexanedione in rat urine. Biomed. Environ. Mass. Spectrom. 14(10):563-572. Fedtke, N., and H.M. Bolt. 1987b. The relevance of 4,5-dihydroxy-2-hexanone in the excre- tion kinetics of n-hexane metabolites in rat and man. Arch. Toxicol. 61(2):131-137. Fühner, H. 1921. The narcotic effects of gasoline and its components (pentane, hexane, heptane, octane) [in German]. Biochem. Z. 115:235-261. Hadjiivanova, N.B., P.Z. Salovski, M.M. Groseva, S.B. Charakchieva, and C.K. Nechev. 1987. Early effects of n-hexane and irradiation on the lung surfactant system. Acta Physiol. Pharmacol. Bulg. 13(3):25-29. Hansen, E. 1992. n-Hexane. Pp. 37-39 in Nordic Criteria for Reproductive Toxicity. Nord 1992:16, Nordic Council of Ministers, Copenhagen, Denmark. Honma, T. 1983. Changes in acetylcholine metabolism in rat brain after a short-term exposure to toluene and n-hexane. Toxicol. Lett. 16(1-2):17-22. Honma, T., M. Miyagawa, M. Sato, and H. Hasegawa. 1982. Increase in glutamine con- tent of rat midbrain induced by short-term exposure to toluene and hexane. Ind. Health 20(2):109-115. Howd, R.A., L.R. Bingham, T.M. Steeger, C.S. Rebert, and G.T. Pryor. 1982. Relation between schedules of exposure to hexane and plasma levels of 2,5-hexanedione. Neurobehav. Toxicol. Teratol. 4(1): 87-91. Ikeda, T., Y. Katakura, R. Kishi, and H. Miyake. 1993. Acute neurobehavioral effects of co-inhalation of toluene and n-hexane on schedule-controlled behavior in rats. En- viron. Res. 63(1):70-81. Krämer, A., H. Staudinger, and V. Ullrich. 1974. Effect of n-hexane inhalation on the monooxygenase system in mice liver microsomes. Chem.-Biol. Interact. 8(1):11- 18. Lam, C.W., T.J. Galen, J.F. Boyd, and D.L. Pierson. 1990. Mechanism of transport and distribution of organic solvents in blood. Toxicol. Appl. Pharmacol. 104(1):117- 129. Lazarew, N.W. 1929. On the toxicity of various hydrocarbon vapours [in German]. Arch. Exp. Pathol. Pharmakol. 143:223-233.

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n-Hexane 107 Lide, D.R.,ed. 1999. CRC Handbook of Chemistry and Physics, 80th Ed. Boca Raton, FL: CRC Press MSZW (Ministerie van Sociale Zaken en Werkgelegenheid). 2004. Nationale MAC-lijst 2004: n-Hexaan. Den Haag: SDU Uitgevers [online]. Available: http://www.las rook.net/lasrookNL/maclijst2004.htm [accessed Feb. 3, 2012]. Mutti, A., M. Falzoi, S. Lucertini, G. Arfini, M. Zignani, S. Lombardi, and I. Franchini. 1984. n-Hexane metabolism in occupationally exposed workers. Br. J. Ind. Med. 41(4):533-538. Nelson, K.W., J.F. Ege, M. Ross, L.E. Woodman, and L. Silverman. 1943. Sensory re- sponse to certain industrial solvent vapors. J. Ind. Hyg. Toxicol. 25(7):282-285. NIOSH (National Institute for Occupational Safety and Health). 1977. Criteria for a Rec- ommended Standard. Occupational Exposure to Alkanes (C5-C8). DHEW (NIOSH) Publication No. 77-151. U.S. Department of Health, Education, and Wel- fare, Public Health Service, Center for Disease Control, National Institute for Oc- cupational Safety and Health, Cincinnati, OH. March 1977 [online]. Available: http://www.cdc.gov/niosh/pdfs/77-151a.pdf [accessed Jan. 17, 2013]. NIOSH (National Institute for Occupational Safety and Health). 1994. Documentation for Immediately Dangerous to Life or Health Concentrations (IDLHs): n-Hexane. U.S. Department of Health and Human Services, Centers for Disease Control and Pre- vention, National Institute for Occupational Safety and Health, Cincinatti, OH [online]. Available: http://www.cdc.gov/niosh/idlh/110543.html [accessed Jan. 17, 2013]. NIOSH (National Institute for Occupational Safety and Health). 2011. NIOSH Pocket Guide to Chemical Hazards: n-Hexane. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occu- pational Safety and Health, Cincinnati, OH [online]. Available: http://www.cdc. gov/niosh/npg/npgd0322.html [accessed Jan. 17, 2013]. Nomiyama, K., and H. Nomiyama. 1974. Respiratory retention, uptake and excretion of organic solvents in man. Int. Arch. Arbeitsmed. 32(1-2):75-83. NRC (National Research Council). 1993. Guidelines for Developing Community Emer- gency Exposure Levels for Hazardous Substances. Washington, DC: National Academy Press. NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: Na- tional Academy Press. NRC (National Research Council). 2012. Butane. Pp. 13-47 in Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol. 12. Washington, DC: National Academies Press. O’Neil, M.J., P.E. Heckelman, C.B. Koch, and K.J. Roman, eds. 2006. n-Hexane. P. 811 in The Merck Index, 14th Ed. Whitehouse Station, NJ: Merck. Perbellini, L., F. Brugnone, and I. Pavan. 1980. Identification of the metabolites of n- hexane, cyclohexane and their isomers in men's urine. Toxicol. Appl. Pharmacol. 53(2):220-229. Perbellini, L., M.C. Amantini, F. Brugnone, and N. Frontali. 1982. Urinary excretion of n-hexane metabolites. A comparative study in rat, rabbit and monkey. Arch. Toxi- col. 50(3-4):203-215. Pryor, G.T., L.R. Bingham, J. Dickinson, C.S. Rebert, and R.A. Howd. 1982. Importance of schedule of exposure to hexane in causing neurotoxicity. Neurobehav. Toxicol. Teratol. 4(1):71-78.

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108 Acute Exposure Guideline Levels Raje, R.R., M. Greening, and M.T. Fine. 1984. Blood n-hexane concentration following acute inhalation exposure in rats. Res. Commun. Chem. Pathol. Pharmacol. 46(2):297-300. Ritchie, G.D., K.R. Still, W.K. Alexander, A.F. Nordholm, C.L. Wilson, J. Rossi III, and D.R. Mattie. 2001. A review of the neurotoxic risk of selected hydrocarbon fuels. J. Toxicol. Environ. Health B Crit. Rev. 4(3):223-312. Schmidt, R., N. Schnoy, H. Altenkirch, and H.M. Wagner. 1984. Ultrastructural altera- tion of intrapulmonary nerves after exposure to organic solvents. A contribution to “sniffers disease” Respiration 46(4):362-369. Schnoy, N., R. Schmidt, H. Altenkirch, and H.M. Wagner. 1982. Ultrastructural altera- tion of the alveolar epithelium after exposure to organic solvents. Respiration 43(3):221-231. Seppalainen, A.M. 1988. Neurophysiological approaches to the detection of early neuro- toxicity in humans. Crit. Rev. Toxicol. 18(4):245-298. Shibata, E., G. Johanson, A. Löf, L. Ernstgård, E. Gullstrand, and K. Sigvardsson. 2002. Changes in n-hexane toxicokinetics in short-term single exposure due to co- exposure to methyl ethyl ketone in volunteers. Int. Arch. Occup. Environ. Health 75(6):399-405. Stoltenburg-Didinger, G. 1991. The effect of pre- and postnatal exposure to organic sol- vents on the development of the cerebellar cortex in the rat. Prog. Histochem. Cy- tochem. 23(1-4):227-234. Stoltenburg-Didinger, G., H. Altenkirch, and M. Wagner. 1990. Neurotoxicity of organic solvent mixtures: Embryotoxicity and fetotoxicity. Neurotoxicol. Teratol. 12(6):585-589. Swann, H.E., B.K. Kwon, G.K. Hogan, and W.M. Snellings. 1974. Acute inhalation toxi- cology of volatile hydrocarbons. Am. Ind. Hyg. Assoc. J. 35(9):511-518. van Engelen, J.G., W. Rebel-de Haan, J.J. Opdam, and G.J. Mulder. 1997. Effect of co- exposure to methyl ethyl ketone (MEK) on n-hexane toxicokinetics in human vol- unteers. Toxicol. Appl. Pharmacol. 144(2):385-395. van Raaij, M.T.M., P.A.H. Janssen, and A.H. Piersma. 2003. The Relevance of Develop- mental Toxicity Endpoints for Acute Limit Setting. RIVM Report 601900004/2003. Ministry of Public Health, Sports and Well-Being, Bilthoven, The Netherlands [online]. Available: http://www.rivm.nl/bibliotheek/rapporten/601900004.html [ac- cessed Jan. 17, 2013]. Veulemans, H., E. van Vlem, H. Janssens, R. Masschelein, and A. Leplat. 1982. Experi- mental human exposure to n-hexane. Study of the respiratory uptake and elimina- tion, and of n-hexane concentrations in peripheral venous blood. Int. Arch. Occup. Environ. Health 49(3-4):251-263. WHO (World Health Organization). 1991. n-Hexane. Environmental Health Criteria 122. International Programme on Chemical Safety, World Health Organization,Geneva, Switzerland [online]. Available: http://www.inchem.org/documents/ehc/ehc/ehc122. htm [accessed Jan. 17, 2013].

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n-Hexane 109 APPENDIX A DERIVATION OF AEGL VALUES FOR n-HEXANE Derivation of AEGL-1 Values Data were insufficient for deriving AGEL-1 values for n-hexane, so no values are recommended. Derivation of AEGL-2 Values In the absence of data for deriving AEGL-2 values for n-hexane and be- cause n-hexane has a steep concentration-response curve, AEGL-2 values were calculating by dividing the AEGL-3 values by 3 (NRC 2001). 10-min AEGL-2: 12,000 ppm ÷ 3 = 4,000 ppm 30-min AEGL-2: 8,600 ppm ÷ 3 = 2,900 ppm 1-h AEGL-2: 8,600 ppm ÷ 3 = 2,900 ppm 4-h AEGL-2: 8,600 ppm ÷ 3 = 2,900 ppm 8-h AEGL-2: 8,600 ppm ÷ 3 = 2,900 ppm Derivation of AEGL-3 Values Key study: Raje, R.R., M. Greening, and M.T. Fine. 1984. Blood n hexane concentration following acute inhalation exposure in rats. Res. Commun. Chem. Pathol. Pharmacol. 46(2):297-300. Toxicity end point: No mortality in rats exposed to n-hexane at 86,222 ppm for 30 min. Time scaling: The 10-min value was time-scaled using the equation Cn × t = k, with n = 3. (8,600 ppm)3 × 30 min = k k = 19.08 × 1012 ppm-min Because a steady-state blood concentration will be reached within 30 min, no increase in effect-size by exposure duration is expected from 30 min to 8 h.

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110 Acute Exposure Guideline Levels Therefore, AEGL-2 values for the 1-h, 4-h, and 8-h durations were set equal to the 30-min AEGL-2 value. Uncertainty factors: 3 for interspecies differences 3 for intraspecies variability 10-min AEGL-3: C3 × 10 min = 19.08 × 1012 ppm-min C ≈ 12,000 ppm (42,000 mg/m3) 30-min AEGL-3: 86,222 ppm ÷ 10 ≈ 8,600 ppm (30,000 mg/m3) (point of departure) 1-h AEGL-3: Set equal to 30-min AEGL-3 of 8,600 ppm (30,000 mg/m3) 4-h AEGL-3: Set equal to 30-min AEGL-3 of 8,600 ppm (30,000 mg/m3) 8-h AEGL-3: Set equal to 30-min AEGL-3 of 8,600 ppm (30,000 mg/m3)

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n-Hexane 111 APPENDIX B CATEGORY PLOT FOR n-HEXANE FIGURE B-1 Category plot of toxicity data on n-hexane compared with AEGL values. Lethal concentrations in animals were not plotted, because the available data were not reliable. Studies reporting lethality in animals used static exposure conditions or animals were exposed under restraint, and had poor descriptions of methods and results (see Sec- tion 7.2 for discussion). TABLE B-1 Data Used in Category Plot Source Species Sex No. Exposures ppm Minutes Category NAC/AEGL-1 NR 10 AEGL NAC/AEGL-1 NR 30 AEGL NAC/AEGL-1 NR 60 AEGL NAC/AEGL-1 NR 240 AEGL NAC/AEGL-1 NR 480 AEGL NAC/AEGL-2 4,000 10 AEGL NAC/AEGL-2 2,900 30 AEGL NAC/AEGL-2 2,900 60 AEGL NAC/AEGL-2 2,900 240 AEGL (Continued)

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112 Acute Exposure Guideline Levels TABLE B-1 Continued Source Species Sex No. Exposures ppm Minutes Category NAC/AEGL-2 2,900 480 AEGL NAC/AEGL-3 12,000 10 AEGL NAC/AEGL-3 8,600 30 AEGL NAC/AEGL-3 8,600 60 AEGL NAC/AEGL-3 8,600 240 AEGL NAC/AEGL-3 8,600 480 AEGL Nelson et al. 1943 Human Both 1 500 5 0 Shibata et al. 2002 Human Male 1 54.2 120 0 Nomiyama and Human Both 1 122 240 0 Nomiyama 1974 Nomiyama and Human Both 1 122 240 0 Nomiyama 1974 Veulemans et al. 1982 Human Male 1 200 240 0 van Engelen et al. 1997 Human Male 1 60 15.5 0 Human Male 1 60 234.6 0 Bus et al. 1982 Rat 1 3,000 360 0 Rat 1 10,000 360 2 Raje et al. 1984 Rat 1 86,222 15 0 Rat 1 86,222 25 2 Pryor et al. 1982 Rat 1 48,000 10 2 For category: 0 = no effect, 1 = discomfort, 2 = disabling, 3 = lethal; L = lethality.

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n-Hexane 113 APPENDIX C ACUTE EXPOSURE GUIDELINE LEVELS FOR n-HEXANE Derivation Summary AEGL -1 VALUES Data were insufficient for deriving AGEL-1 values for n-hexane, so no values are recommended. AEGL-2 VALUES 10 min 30 min 1h 4h 8h a a a a 4,000 ppm 2,900 ppm 2,900 ppm 2,900 ppm 2,900 ppma (14,000 (10,000 (10,000 (10,000 (10,000 mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) Data adequacy: Data are not available to define the concentration-response curve for n-hexane. A steep concentration-response relationship is observed for butane, a structural analog of n-hexane and CNS depressant (NRC 2012), so a similar relationship is expected for n-hexane. For chemicals with a steep concentration- response curve, AEGL-2 values may be derived by reducing AEGL-3 values by one-third (NRC 2001). Therefore, AEGL-2 for values n-hexane were calculated by dividing the AEGL-3 values by 3. a The AEGL-2 value is higher than 10% of the lower explosive limit of n-hexane in air of 1.1% (11,000 ppm). Therefore, safety considerations against the hazard of explosion must be taken into account. AEGL-3 VALUES 10 min 30 min 1h 4h 8 hr See belowa See belowb See belowb See belowb See belowb Key reference: Raje, R.R., M. Greening, and M.T. Fine. 1984. Blood n hexane concentration following acute inhalation exposure in rats. Res. Commun. Chem. Pathol. Pharmacol. 46(2):297-300. Test species/Strain/Number: Rat, Sprague-Dawely, groups of 4 male Exposure route/Concentrations/Durations: Inhalation, 86,222 ppm for 10, 15, 20, 25, or 30 min. Effects: Duration (min) Effects 10 No effects 15 No effects 20 No effects 25 Ataxia, no deaths 30 Ataxia, no deaths (Continued)

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114 Acute Exposure Guideline Levels AEGL-3 VALUES Continued End point/Concentration/Rationale: Absence of mortality. Uncertainty factors/Rationale: Total uncertainty factor: 10 Interspecies: 3 Intraspecies: 3 A total uncertainty factor of 10 was considered sufficient because the effects are attributed to n-hexane itself and no relevant differences in kinetics are assumed. Mortality from n-hexane exposure is preceded by CNS depression, and variation in susceptibility for CNS-depressing effects is not very great in the human population. Modifying factor: None Animal-to-human dosimetric adjustment: Not applicable Time scaling: Because a steady-state blood concentration will be reached within 30 min of exposure, no increase in effect-size by exposure duration is expected from 30 min to 8 h. Therefore, the AEGL-3 values for the 1-h, 4-h, and 8-h durations are set equal to the 30-min AEGL-3 value. The 10-min AEGL-3 value was derived from the 30-min AEGL-3 value by time-scaling using the equation Cn × t = k, with n = 3. Data adequacy: The database is very poor. Available data for derivation of AEGL-3 values were predominantly from toxicokinetics studies. Adequate toxicity studies are lacking. a The 10-min AEGL-3 value of 12,000 ppm (42,240 mg/m3) is higher than the lower ex- plosive limit of n-hexane in air of 1.1% (11,000 ppm). Therefore, extreme safety consid- erations against the hazard of explosion must be taken into account. b The AEGL-3 values for the 30-min, 1-h, 4-h, and 8-h durations are each 8,600 ppm (30,000 mg/m3), which is higher than 50% of the lower explosive limit of n-hexane in air of 1.1% (11,000 ppm). Therefore, extreme safety considerations against the hazard of explosion must be taken into account.